Brain antinociception

In further support of a pro-nociceptive role of CX3CL1 are data showing that the direct injection of CX3CL1 in the periaqueductal grey, a brain region mostly involved with analgesic responses, albeit un-effective by itself, results in inhibition of the antinociceptive effects induced by p, 5, and k opioid agonists (Chen et al. 2(X)7). 

Chen X, Geller EB, Rogers TJ, Adler MW (2007) The chemokine CX3CLl/fractaUdne interferes with the antinociceptive effect induced by opioid agonists in the periaqueductal grey of rats. Brain Res 1153 52-57... 

Tables 6.8-6.11 illustrate the wide range of C3 side-chain modified A -THC analogues that have been reported in the literature, together with associated in vitro and in vivo data. The affinity of classical cannabinoid analogues for the CBi receptor has been shown to correlate with depression of spontaneous activity and the production of antinociception, hypothermia and catalepsy in mice, and with psychomimetic activity in humans [93]. However, in some cases, there were unexplained differences between the observed trends in binding affinity and the trends in activity in mouse behavioural models. This may point to differences in efficacy among full agonists, partial agonists and antagonists/inverse agonists, or may reflect differences in in vivo metabolism or blood-brain barrier penetration or a combination of these factors.

Noladin ether (3) was recently isolated from porcine brain [16] and found to bind to the CBi receptor (/fj = 21.2 nM), to bind weakly to the CB2 receptor K, > 3 /iM) and it causes typical cannabinoid-like effects such as sedation, hypothermia, intestinal immobility and mild antinociception in mice [16]. This endocannabinoid had previously been synthesised independently by both Mechoulam and co-workers [176] and Sugiura et al. [173]. SAR studies of this endocannabinoid are lacking in the literature, however, a recent publication highlighted the importance of the tetra-unsaturated C20 chain... 

Histamine also induces antinociceptive (i.e. pain-relieving) responses in animals after microinjection into several brain regions [73, 74]. H, and H2 mechanisms are significant and both neuronal and humoral mechanisms may be involved. Brain H2 receptors appear to mediate some forms of endogenous analgesic responses, especially those elicited by exposure to stressors [75]. Many of the modulatory actions of histamine discussed above appear to be activated as part of stress responses. For reasons that remain unclear, histamine releasers, such as thioperamide, show only mild, biphasic antinociceptive actions, even though histamine is a potent and effective analgesic substance. Outside the brain, both H and H3 receptors exist on certain types of sensory nerves and activation of these receptors promotes and inhibits, respectively, peripheral nerve transmission related to pain and/or inflammation [76,77]. 

Sawynok, J., Reid, A. and Isbrucker, R. Adenosine mediates calcium-induced antinociception and potentiation of noradrenergic antinociception in the spinal cord. Brain Res. 524 187-195,1990. 

Yaksh, T. L. (1979) Direct evidence that spinal serotonin and noradrenaline terminals mediate the spinal antinociceptive effects of morphine in the central periaqueductal gray. Brain Res.. 160 180-185. 

Findings continue to accumulate in the field of endogenous opiates, as exemplified by two tetrapeptides isolated from mammalian brain and found to have high affinity and selectivity for p-opioid receptors. These tetrapeptides are endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2). A number of synthetic analogues have been prepared with the view to improve their metabolic stability and, in some cases, to limit their access to peripheral opioid receptors. The three synthetic endomor-phin analogues Tyr-D-Ala-Phe-Phe-NH2 (6.84), Tyr-D-Arg-Phe-Phe-NH2 (6.85), and Tyr-D-Arg-Phe-Ape-NH2 (6.86), to be discussed in the next section, have potent antinociceptive effects in in vivo inflammatory tests but exhibit modest effects in the CNS. However, and despite the presence of a D-amino acid and a protected C-terminus, they remained sensitive to enzymatic hydrolysis [211][212],... 

Alhaider AA. (1991). Antinociceptive effect of ketanserin in mice invoivement of supraspinai 5-HT2 receptors in nociceptive transmission. Brain Res. 543(2) 335-40. 

Kiritsy-Roy JA, Shyu BC, Danneman PJ, Morrow TJ, Beiczynski C, Casey KL. (1994). Spinai antinociception mediated by a cocaine-sensitive dopaminergic supraspinai mechanism. Brain Res. 644(1) 109-16. 

Lichtman AH, Martin BR. (1991). Cannabinoid-induced antinociception is mediated by a spinal alpha 2-noradrenergic mechanism. Brain Res. 559(2) 309-14. 

Pugh G Jr, Abood ME, Welch SP. (1995). Antisense oligodeoxynucleotides to the kappa-1 receptor block the antinociceptive effects of delta 9-THC in the spinal cord. Brain Res. 689(1) 157-58. 

Bhargava HN, Cao YJ. (1997). Effects of noribogaine on the development of tolerance to antinociceptive action of morphine in mice. Brain Res. 771(2) 343-46. 

Cao YJ, Bhargava HN. (1997). Effects of ibogaine on the development of tolerance to antinociceptive action of mu-, delta-, and kappa-opioid receptor agonists in mice. Brain Res. 752(1-2) 250-4. Cappendijk SL, Dzoijic MR. (1993). Inhibitory effects of ibogaine on cocaine self-administration in rats. EurJ Pharmacol. 241(2-3) 261-65. 

Craft RM, MUholland RB (1998) Sex differences in cocaine- and nicotine-induced antinociception in the rat. Brain Res 809 137-140... 

Wilcox GL, Carlsson KH, Jochim A, Jurna 1 (1987) Mutual potentiation of antinociceptive effects of morphine and clonidine in rat spinal cord. Brain Res 405 84-93... 

Brain cannabinoid receptor. In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration, and impairment of memory. The cognitive deficiencies persist after withdrawal. The toxicity of cannabis has been underestimated for a long time, since recent findings revealed that A-9-THG-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus. The acute effects of cannabinoids, as well as the development of tolerance, are mediated by G protein-coupled cannabinoid receptors. The CBl receptor and its splice variant, CBl A, are found predominantly in the brain with highest densities in the hippocampus, cerebellum, and striatum. The CB2 receptor is found predominantly in the spleen and in hemopoi-... 

All five muscarinic receptor subtypes have been detected in the central nervous system. The roles of Mx through M3 have been analyzed by means of experiments in knockout mice. The Mx subtype is richly expressed in brain areas involved in cognition. Knockout of Mx receptors was associated with impaired neuronal plasticity in the forebrain, and pilocarpine did not induce seizures in Mx mutant mice. The central nervous system effects of the synthetic muscarinic agonist oxotremorine (tremor, hypothermia, and antinociception) were lacking in mice with homozygously mutated M2 receptors. Animals lacking M3 receptors, especially those in the hypothalamus, had reduced appetite and diminished body fat mass. 

Serotonin is also involved in opioid effects on the transmission and processing of nociceptive information at a level rostral to the PAG. Borszcz (1999) and Borszcz and Streltsov (2000) have demonstrated that the antinociceptive effect of morphine administered into the PAG can be attenuated be serotonin antagonism in the central nucleus of the amygdala and the parafascicular nucleus of the thalamus, suggesting that serotonin is also involved in pain processing in higher brain centers. 

Hamalainen, M. M. and Pertovaara, A. The antinociceptive action of an alpha2 adrenoceptor agonist in the spinal horn is due to a direct spinal action and not to activation of descending inhibition, Brain Res. Bull. 1995, 37, 581-587. 

Kang, Y., Zhang, C., Qiao, J. Involvement of endogenous opioids and ATP-sensitive potassium channels in the mediation of carbachol-induced antinociception at the spinal level a behavioral study in rats, Brain Research 1997, 761, 342-346. 

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